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Sequential Therapy in Renal Cell Carcinoma
J C Nunes Marques
Serviço de Oncologia Médica
Centro Hospitalar de Lisboa Ocidental
Molecular Pathways and Targeted Therapies in Renal-Cell Carcinoma.
Brugarolas J. N Engl J Med 2007;356:185-187.
Angiogenesis: a target for anticancer therapy
Rini. Clin Cancer Res 2007, 13
Faivre et al. Nat Ver Drug Disc 2007, 6
Homsi and Dand. Cancer control 2007, 14
Andrae et al. Genes Dev 2008, 22
Kerbel. N Engl J Med 2008, 358
Sonpavde et al. Expert Opin Investig Drugs 2008, 17
Ma and Adjei. CA Cancer J Clin 2009, 59
Chronology and uses of available molecular-targeted agents in metastatic
renal cell carcinoma in the U.S. and Europe.
Hutson T E The Oncologist 2011;16:14-22
Ongoing Phase III Trial:
Pazopanib vs Sunitinib
in the first-line treatment of patients with mRCC
(COMPARZ)
US National Institutes of Health Web Site
http://www.clinicaltrials.gov/ct2/show/NCT00720941
acessed26oct2011
Potencial Biomarkers in mRCC
Speculation of the best sequential therapy for mRCC
PFS of patients receiving sequential therapy (months)
Sunitinib2
11
Sorafenib14
4,5
Everolimus15
4
Bevacizumab+INF4
10,2
Sorafenib1
6
Sunitinib14
6,5
Everolimus15
4
27,1
Bevacizumab+INF4
10,2
Sunitinib12
7
Sorafenib14
4,5
Everolimus15
4
25,7
INF2
5
Axitinib10
15,7
Everolimus15
4
Bevacizumab+INF4
10,2
Sorafenib1
6
Axitinib13
7,4
1 Escudier et al. NEngJMed 2007; 356
2 Motzer et al. NEngJMed 2007; 356
4 Escudier et al. Lancet 2007; 370
10 Rixe et al. Lancet Oncol 2007; 8
12 Scharzberg et al. J Clin Oncol 2008; 26
13 Rini BI et al. J Clin Oncol 2008; 26
14 Rini BI et al. J Clin Oncol 2007; 25
15Sablin MP et al. J Clin Oncol 2007; 25
Total PFS
19,5
24,7
Everolimus15
4
27,6
Escudier B, et al. Cancer 2009; 115 (10 Suppl): 2321-2326
Rational of sequential therapy
• each targeted agent possesses a unique biologic
profile
• patients have benefited from subsequent therapy with
a different antiangiogenic agent
• full dose of each drug can be delivered without
overlapping toxicities
•additional PFS benefit can been achieved
• the aim of therapy is to maximize the overall benefit
to patient in terms of both quality and duration of life
Sablin MP, et al. J Clin Oncol. 2007;25 (18S): Abstract 5038
Dham A, et al. J Clin Oncol. 2007;25(18S):Abstract 5106
Drabkin HÁ, et al. J Clin Oncol.2007;25(18S):Abstract 5041
Targeted agents in sequence
Study*
NCT00903175
(RECORD-3)
Sequence
NCT00732914
(SWITCH)
Study type
Randomized
phase III
Randomized
phase III
NCT00678392
(AXIS)
Randomized
phase III
NCT00474786
(TORISEL 404)
Randomized
phase III
NCT00678288
Randomized
phase II
After 1st line
failure
Treatment 1
Treatment 2
n
Sunitinib
Everolimus
390
vs
everolimus
sunitinib
Sunitinib
Sorafenib
540
vs
sorafenib
sunitinib
650
TT or CK
Sorafenib
vs
axitinib
480
sunitinib
Sorafenib
vs
temsirolimus
Sorafenib
vs
24
sunitinib
Sorafenib+INF
NCT00782275
Phase II
TKI(one), CK
or chemo
Bevacizumab
+temsirolimus
46
NCT00651482
Phase II
TKI (one)
CK
Bevacizumab
+ everolimus
30
*available at http://clinicaltrials.gov
Summary
• The sequential approach with targeted agents have
revealed clinical efficacy
•Data suggests that there is only negligibile crossresistance between TKIs
• In clinical studies of sequential therapy, everolimus
was effective after treatment with one or two TKIs
• In clinical studies of sequential therapy, sequential
treatment was tolerable and toxicity was predictable